Age-Dependent Impairment of Cognitive and Synaptic Function in the htau Mouse Model of Tau Pathology
Open accessAbstract
A hallmark feature of Alzheimer's disease pathology is the presence of neurofibrillary tangles (NFTs), which are intracellular aggregates of conformationally abnormal and hyperphosphorylated tau. The presence of NFTs in the forebrain is associated with impairments of cognitive function, supporting a central role for tau in dementia. The significance of the accumulation of NFTs for neuronal and cognitive function is still obscure. It is possible that NFTs disrupt synaptic transmission and plasticity, leading to memory deficits and cognitive malfunction. To elucidate the relationship between the development of tau pathology and synaptic and cognitive functions, we performed behavioral tests and electrophysiological experiments in the htau mouse. Here we report age-dependent cognitive and physiological impairments in htau mice that preceded neurodegeneration. Twelve-month-old htau mice with moderate tau pathology, but not 4-month-old mice with early-stage tau pathology, presented cognitive deficits in an object recognition memory task in which the visual recognition memory of a novel object was disrupted. Moreover, only 12-month-old htau mice exhibit spatial memory deficits, as indicated by the impaired performance in the Morris water maze. In addition, we report that basal synaptic transmission and induction of long-term potentiation with high-frequency stimulation, but not theta burst stimulation, is perturbed in hippocampal CA1 region of old but not young htau mice. Our results suggest that tau pathology may underlie an age-dependent learning impairment through disruption of synaptic function.
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Mouse models over-expressing WT or mutant tau exhibit progressive neurodegeneration.
“These models also exhibit progressive neurodegeneration, which is consistent with observations in humans that cognitive loss is more closely associated with tau pathology than Aβ pathology (Lewis et al., 2000; Ramsden et al., 2005; Polydoro et al., 2009).”
From β-amyloid accumulation enhances microtubule associated protein tau pathology in an APPNL-G-F/MAPTP301S mouse model of Alzheimer’s disease (2024) · cites this paper as Polydoro et al., 2009
The Introduction reports age-related cortical thinning and fewer detectable nuclei in htau mice carrying nonmutant human tau. The Discussion reports neural loss in a mutant-tau mouse model. These passages support neurodegeneration in both kinds of model, but they do not establish that the mice overexpress tau. (LLM, conf=0.83)
Experimental — accuracy not yet measuredhTau mice exhibit various behavioral and cognitive impairments by 20 months of age.
“Previous studies have suggested that hTau mice exhibit various behavioral and cognitive impairments by 20 months of age [52].”
From Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology (2016) · cites this paper as [52]
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- Authors
- Polydoro, M., Acker, C. M., Duff, K., Castillo, P. E., & Davies, P.
- Affiliations
- Albert Einstein College of Medicine (US)
- Columbia University (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-08-26
- Volume
- 29
- Issue
- 34
- Pages
- 10741-10749
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2760256
- OpenAlex
- W2048865592
- Cited by
- 329
- References
- 34
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 13 · 2023: 22 · 2022: 20 · 2021: 23 · 2020: 24 · 2019: 15 · 2018: 26 · 2017: 19 · 2016: 18 · 2015: 24 · 2014: 25 · 2013: 20 · 2012: 17
- FWCI
- 12.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (R01AG022102)
- National Institute of Neurological Disorders and Stroke (P01NS048447, NS048447)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- tau pathology, Alzheimer's disease, neurofibrillary tangles, cognitive impairment, object recognition memory, spatial memory, synaptic transmission, long-term potentiation, theta burst stimulation, hippocampal CA1, synaptic plasticity
- MeSH terms
- Age Factors, Aging, Analysis of Variance, Animals, Cognition Disorders, Disease Models, Animal, Electric Stimulation, Exploratory Behavior, Hippocampus, Mice, Inbred C57BL, Neuropsychological Tests, Synapses, Neurofibrillary Tangles, tau Proteins, Long-Term Potentiation, Pyramidal Cells, Mice, Knockout, Maze Learning, Excitatory Postsynaptic Potentials, Recognition, Psychology, Tauopathies, Mice, Dual Specificity Phosphatase 2, In Vitro Techniques
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